Roles of short-chain fatty acids in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis

Table 1 The function of short-chain fatty acids in immune regulation during metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis

SCFAs	Immune cells	Function	Ref.
Acetate	Macrophages	A lower dose (0.1 mmol/L) of sodium acetate promotes macrophage inflammation (RAE264.7 cells and Kupffer cells) by promoting the phosphorylation of NF-κB p65 and c-Jun (transcription factor Jun), whereas a higher dose (2 mmol/L) of sodium acetate showed the opposite effect	[39]
Acetate	Macrophages	Sodium acetate-loaded liposomes effectively inhibited lipopolysaccharide-activated Kupffer cell proinflammation	[41]
Acetate	CD8+ T cells	Acetate can promote the conversion of liver-resident CXCR6+ CD8+ T cells to cytotoxic, auto-aggressive CD8+ T cells in MASH liver, promoting liver damage	[42]
Butyrate	Macrophages	Sodium butyrate can inhibit hepatic monocyte-derived macrophage infiltration and promote the apoptosis of proinflammatory M1 macrophages while activating the M2-like macrophages in MASH livers, thereby leading to the healing process	[44]
Butyrate	NK cells	Gut bacteria-derived butyrate can promote the maturation of mouse and human liver-resident NK cells by increasing the expression levels of IFN-γ and CD107a, through IL-18 production in hepatocytes and Kupffer cells	[45]
Butyrate	CD8+ T cells	Gut microbiota-induced butyrate is responsible for the successful transition from activated CD8+ T cells to memory CD8+ T cells and maintains the survival of memory precursors of CD8+ T cells	[47]
Butyrate	CD4+ T cells	Sodium butyrate can promote CD4+ T cell differentiation towards Th2, Th22, and Tregs	[54]
Propionate	Macrophages	Propionic acid can suppress M1 macrophage polarization by inhibiting MAPK signaling pathway	[55]
Propionate	γδ T cells	Propanoic acid derived from gut microbiota can suppress liver inflammation by decreasing the IL-17-producing γδ T cells	[56]
Propionate	T helper cells	Propionate alone or in combination with acetate reduced the numbers of Th1 and Th17 cells and increased the number of Tregs in the spleens and mesenteric lymph nodes of HFD-fed mice	[64]

HFD: High-fructose diet; SCFAs: Short-chain fatty acids; MASH: Metabolic dysfunction-associated steatohepatitis; NK: Natural killer.

Table 2 Clinical trials in the treatment of metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis

Clinical trials	Phase	Disease	Treatment	Measurements
NCT05654805	N/A	MASLD	Oat-fiber supplementation	Fermentation to short-chain fatty acids (SCFAs)
NCT05523024	N/A	MASLD	Dietary supplementation of probiotics; Dietary supplementation of Berberine; Dietary supplementation of Probiotics and Berberine	The concentrations of SCFAs in stool
NCT05402449	N/A	MASLD	Dietary supplementation of probiotics, including Lactobacillus reuteri GMNL-263 (heat-killed) and GMNL-89 (alive), and Lactobacillus rhamnosus GMNL-74 (alive)	Concentrations of SCFAs in blood
NCT04594954	N/A	MASLD	Fecal microbiota transplantation	Production of SCFAs
NCT04415632	N/A	MASLD	Low glycemic index diet; High glycemic index diet	Plasma concentrations of SCFAs
NCT04117802	N/A	MASLD	Maple syrup	Change of fecal SCFAs
NCT01856465	N/A	MASLD	Bariatric surgery	Change of fecal SCFAs
NCT05463575	2	MASLD	Ketohexokinase inhibition	Change of fecal SCFAs, including acetate, propionate, and butyrate
NCT05821010	2	MASH	Lyophilized fecal microbiota transplantation capsules Anaerobutyricum soehngenii; Pasteurized Akkermansia muciniphila; Bifidobacterium animalis subsp. Lactis; Fructo-oligosaccharides	Concentrations of SCFAs in blood (i.e., acetate, butyrate, and propionate)
NCT05647915	4	Obesity MASLD	Berberine plus lifestyle intervention	Change of SCFAs
NCT04465032	4	MASLD	Gut microbiome transplantation	Production of SCFAs

MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; SCFAs: Short-chain fatty acids.